JAK belongs to a family of tyrosine kinases that are involved in inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations and/or diseases associated with hypersecretion of IL6. The present invention also provides methods for the production of the compounds, pharmaceutical compositions comprising the compounds, methods for the prophylaxis and/or treatment of diseases involving inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations and/or diseases associated with hypersecretion of IL6 by administering a compound of the present invention.
Janus kinases (JAK) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members are described in the prior art: JAK1, JAK2, JAK3 and TYK2. Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs and then migrate to the nucleus to modulate transcription. JAK-STAT intracellular signal transduction is suitable for the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker W. et al. (2008)).
The combination of genetic models and small molecule JAK inhibitor research revealed the therapeutic potential of several JAKs. JAK3 is validated by mouse and human genetics as an immune-suppression target (O'Shea J et al. (2004)). JAK3 inhibitors were successful taken into clinical development, initially for organ transplant rejection but later also in other immuno-inflammatory indications such as rheumatoid arthritis (RA), psoriasis and Crohn's diseases (http://clinicaltrials.gov/). TYK2 is a potential target for immuno-inflammatory diseases, being validated by human genetics and mouse knock-out studies (Levy D. and Loomis C. (2007)). JAK1 is a new target in the immuno-inflammatory disease area. JAK1 heterodimerizes with other JAKs to transduce cytokine-driven pro-inflammatory signaling. Therefore, it is expected that inhibition of JAK1 and other JAKs are a therapeutic benefit for a series of inflammatory diseases and other diseases driven by JAK-mediated signal transduction.